Zou Min, Toivanen Roxanne, Mitrofanova Antonina, Floch Nicolas, Hayati Sheida, Sun Yanping, Le Magnen Clémentine, Chester Daniel, Mostaghel Elahe A, Califano Andrea, Rubin Mark A, Shen Michael M, Abate-Shen Cory
Departments of Medicine and Urology, Institute of Cancer Genetics, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York.
Departments of Medicine and Genetics and Developmental Biology, Institute of Cancer Genetics, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York.
Cancer Discov. 2017 Jul;7(7):736-749. doi: 10.1158/2159-8290.CD-16-1174. Epub 2017 Apr 14.
Current treatments for castration-resistant prostate cancer (CRPC) that target androgen receptor (AR) signaling improve patient survival, yet ultimately fail. Here, we provide novel insights into treatment response for the antiandrogen abiraterone by analyses of a genetically engineered mouse (GEM) model with combined inactivation of and , which are frequently comutated in human CRPC. These NPp53 mice fail to respond to abiraterone and display accelerated progression to tumors resembling treatment-related CRPC with neuroendocrine differentiation (CRPC-NE) in humans. Cross-species computational analyses identify master regulators of adverse response that are conserved with human CRPC-NE, including the neural differentiation factor , which promotes neuroendocrine differentiation in cells derived from NPp53 tumors. Furthermore, abiraterone-treated NPp53 prostate tumors contain regions of focal and/or overt neuroendocrine differentiation, distinguished by their proliferative potential. Notably, lineage tracing provides definitive and quantitative evidence that focal and overt neuroendocrine regions arise by transdifferentiation of luminal adenocarcinoma cells. These findings underscore principal roles for and inactivation in abiraterone resistance and progression from adenocarcinoma to CRPC-NE by transdifferentiation. Understanding adverse treatment response and identifying patients likely to fail treatment represent fundamental clinical challenges. By integrating analyses of GEM models and human clinical data, we provide direct genetic evidence for transdifferentiation as a mechanism of drug resistance as well as for stratifying patients for treatment with antiandrogens. .
目前针对去势抵抗性前列腺癌（CRPC）的靶向雄激素受体（AR）信号通路的治疗方法可提高患者生存率，但最终仍会失败。在此，我们通过对一种基因工程小鼠（GEM）模型进行分析，对抗雄激素阿比特龙的治疗反应提供了新的见解，该模型同时失活了 和 ，这两个基因在人类CRPC中经常同时发生突变。这些NPp53小鼠对阿比特龙无反应，并显示出加速进展为类似于人类具有神经内分泌分化的治疗相关CRPC（CRPC-NE）的肿瘤。跨物种计算分析确定了与人类CRPC-NE保守的不良反应的主调控因子，包括神经分化因子 ，它促进源自NPp53肿瘤的细胞中的神经内分泌分化。此外，经阿比特龙治疗的NPp53前列腺肿瘤包含局灶性和/或明显神经内分泌分化区域，其增殖潜能不同。值得注意的是，谱系追踪提供了确凿的定量证据，表明局灶性和明显的神经内分泌区域是由管腔腺癌细胞的转分化产生的。这些发现强调了 和 失活在阿比特龙耐药以及通过转分化从腺癌进展为CRPC-NE中的主要作用。了解不良治疗反应并识别可能治疗失败的患者是基本的临床挑战。通过整合GEM模型分析和人类临床数据，我们提供了直接的遗传学证据，证明转分化是耐药机制以及对患者进行抗雄激素治疗分层的依据。
